A Phase II Double-Blind Placebo-Controlled Trial of Dronabinol and BRENDA for the Treatment of Cannabis Withdrawal

Trial Information

A Phase II Double-Blind Placebo-Controlled Trial of Dronabinol and BRENDA for the Treatment of Cannabis Withdrawal

1. Background: Cannabis is the most widely used illicit drug in the U.S. According to the
2004 U.S. The 2004 NSDUH estimates there are 3.2 million daily or almost daily marijuana
smokers in the United States. Recent reports have estimated that 1.5% of the US population
meets DSM-IV diagnostic criteria for cannabis abuse or dependence, with the sharpest
increases among young black men and women and young Hispanic men (2). Cannabis users
commonly endorse adverse psychosocial and medical effects from their cannabis use, which
include dysphoria, loss of control over use, cognitive impairment, and strained social
relationships.

In humans, the cannabis withdrawal syndrome is a constellation of affective and behavioral
symptoms that occur within 24 to 48 hours after abrupt cessation of marijuana use with a
gradual return to baseline after 1-2 weeks. A recent review of the literature on cannabis
withdrawal identified consistent reports of anxiety, irritability, physical discomfort,
insomnia, and appetite suppression to be associated with abrupt cessation of cannabis use in
heavy users across controlled inpatient and outpatient trials.

The agonist dronabinol (Marinol) has shown promise in the prevention of cannabis withdrawal
in human lab studies and its reported amelioration of anxiety, misery, insomnia, drug
craving and appetite suppression from abrupt cannabis cessation provides the rationale for
its use as an agent to prevent cannabis withdrawal in an outpatient, treatment seeking
population(9). Dronabinol has also been used as a brief "maintenance" treatment in a
cannabis self-administration study in humans. Currently, dronabinol is indicated for
treatment of AIDS-related anorexia and nausea associated with cancer chemotherapy. Two
principle aims of our proposal are therefore to gain familiarity with cannabis withdrawal in
a naturalistic outpatient treatment setting and compare an agonist therapy to placebo to
attenuate cannabis withdrawal and enhance treatment outcome.

The general pattern of low rates of total abstinence and lack of significant differences
between high intensity psychotherapy treatment vs. low intensity and voucher-based treatment
holds across all psychosocial treatment studies. In keeping with prior evidence supporting
the relative efficacy of brief interventions for cannabis dependence, the current proposal
will apply a well-established brief medicalized psychotherapy known as B.R.E.N.D.A. for the
treatment of cannabis dependence.

To date, studies evaluating cannabis patients have primarily focused on identifying
neurotoxic drug effects such as impaired learning, memory, attention and executive function.
We propose to more fully examine the behaviors with relevance to addiction vulnerability and
relapse. Such behaviors include but are not limited to poor inhibition, high risk-taking,
positive affective bias toward drug stimuli, poor affect regulation, and poor
decision-making. We plan to utilize standardized tasks and questionnaires to objectively
characterize dimensions of these addiction relevant behaviors in cannabis patients and to
examine the effect of cannabis withdrawal and dronabinol treatment on these behavioral
measures. We will also correlate brain differences (structural and functional) with
behavioral measures in cannabis dependent patients before and after treatment with
dronabinol as compared to placebo.

The search for effective treatment of addictive disorders is limited by our incomplete
knowledge about the brain substrates critical for addiction and for addiction recovery. The
recent use of PET and fMRI has allowed researchers to examine connections between brain
activity and vulnerability to addiction and relapse. In marijuana users, PET and fMRI
techniques have been used to study regional brain volumes, blood flow, metabolism. However,
understanding cue induced craving is more immediately relevant to treatment and relapse
prevention in cannabis addiction since cannabis users have a high rate of relapse compared
to those found for other drugs of abuse. In addiction, cues that have been consistently
associated with drug reward can trigger craving for the drug. Clinically, the craving for
the drug is sufficiently compelling in many cases to precipitate a relapse despite
significant effort on the patient's part to maintain abstinence and despite significant
negative consequences. Although PET and fMRI techniques have been successfully used to
study cue induced craving in other drugs of abuse (e.g. cocaine) leading to greater
understanding of the mechanism of relapse (limbic activation in response to drug cues),
these techniques have not been utilized in cannabis patients. Several preliminary studies
used patient self-report to demonstrate cue induced craving in cannabis patients. We propose
to utilize physiological measures and functional neuroimaging to objectively demonstrate
cue-induced craving in cannabis dependent subjects and to identify the brain substrates that
mediate this craving. Similarly, dronabinol reduced self-reported drug craving in one
recent human laboratory study. We propose to examine whether dronabinol will change
physiological measures and brain activation in response to drug cues.

2. Study objectives:

1. To evaluate the cannabis withdrawal syndrome in a naturalistic outpatient setting as
one possible cause for the low rates of total abstinence seen in our trial and all
other clinical trials of adult cannabis dependence.

1. Primary Hypothesis: Poor performance on neurocognitive tasks and questionnaires
will be correlated with duration and amount of cannabis use.

2. Secondary Hypothesis: Cannabis withdrawal will be correlated with impaired
performance on neurocognitive tasks and questionnaires. Dronabinol treatment
will reduce this impairment on tasks of affect regulation and affective bias/drug
preference compared to placebo.

1. Primary Hypothesis: Cue-induced craving will be positively correlated with
changes in physiological measures and increased amygdalar activation and
negatively correlated with prefrontal activation in cannabis dependent patients
during cannabis discontinuation, and dronabinol treatment will reduce the
intensity of cue- induced physiological changes and brain activation compared to
placebo.

2. Secondary Hypotheses: Measures of prefrontal cortex gray matter and resting
perfusion in prefrontal cortex, cingulate cortex and amygdala will be positively
correlated with performance on neurocognitive tasks and questionnaires as well as
treatment outcome.

3. Location: This is a single site study. All patient recruitment and data collection will
occur at the Treatment Research Center at the University of Pennsylvania, 3900 Chestnut
Street, Philadelphia, PA 19104, except for the Neuroimaging which will take place at the
HUP6 fMRI in the basement of the Hospital of the University of Pennsylvania, 34th and Spruce
Streets, Philadelphia, PA 19104.

STUDY DESIGN

4. Research design & methodology: This is a Phase 2 double blind placebo controlled trial.
We will recruit 60 cannabis dependent subjects and treat them with the combination of
dronabinol 10mg QID (four times per day) and BRENDA or placebo qid (four times per day) and
BRENDA to reduce their consumption of cannabis. Subjects will be 60 men and women with
current DSM-IV diagnosis of cannabis dependence. All patients will receive six sessions of
BRENDA at visits 1, 3, 6, 9, 11, and 12. The study length for each patient will be one week
for screening and baseline self-report and neurocognitive battery measures. Patients who
qualify will be offered an opportunity to participate in the fMRI portion of the study with
baseline fMRI obtained in the first week prior to starting medications and second fMRI
obtained during week two of medications. This is followed by 3 weeks of medication and,
after completing medications, three additional weekly visits (two for BRENDA and one for
final assessment).

5. Duration: Each subject will participate in a 7 week treatment trial with the following
schedule of visits: STUDY VISITS

Week 1 (Baseline Measures):

Week 2 - 4 (Medication Treatment):

Weeks 5-6 (Medication Washout)

Week 7 (Final Visit):

We anticipate that we will require two years to complete data collection with 60 subjects
and will require one year for data analysis. Thus, the proposed study will be completed in
approximately three years.

SUBJECT SELECTION & WITHDRAWAL

Inclusion Criteria:

1. Males and females, 18-55 years old

2. Meets DSM-IV criteria for Cannabis Dependence

3. History of chronic cannabis use of moderate intensity defined by 10 or more years of
use with an average frequency of 2 or more joints/day on 5 or more days/week

4. Live within a commutable distance of the Treatment Research Center

5. Understand and sign the informed consent

6. Voluntarily seeking treatment for cannabis dependence

Exclusion Criteria:

1. Current DSM-IV diagnosis of any psychoactive substance dependence other than
marijuana, or nicotine dependence

2. Concomitant treatment with sedative hypnotics, opioid analgesics or other known CNS
depressants at a dose and frequency that is unacceptable to the principal
investigator

3. Mandated to treatment based upon a legal decision or as a condition of employment

4. Current severe psychiatric symptoms, e.g. psychosis, dementia, acute suicidal or
homicidal ideation, mania or depression requiring antidepressant therapy, or which
could make it unsafe for the patient to participate in the opinion of the primary
investigators

8. Has any disease of the gastrointestinal system, liver or kidneys which could result
in altered metabolism or excretion of the study medication (history of major
gastrointestinal tract surgery, gastrectomy, gastrotomy, bowel resection, etc.) or
history of chronic gastrointestinal disorders (ulcerative colitis, regional
enteritis, or gastrointestinal bleeding)

9. Female subjects who are pregnant or lactating, or female subjects of child bearing
potential who are not using acceptable methods of birth control. Acceptable methods
of birth control include:

Subjects who are selected for the clinical trial based on above inclusion and exclusion
criteria will be screened further with the following exclusion criteria for possible
participation in the fMRI imaging session:

1. Participation in a clinical trial and receipt of investigational drug(s) other than
this clinical trial during previous 60 days.

2. History of serious head trauma or injury causing loss of consciousness that lasted
more than 3 minutes.

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